Human chorionic gonadotropin, its free subunits and gestational trophoblastic disease.

Monoclonal antibody-based immunoassays can detect specifically intact human chorionic gonadotropin (hCG), the free alpha-subunit and the free beta-subunit. The differential production of hCG and its free subunits is important in gestational trophoblastic disease. Using well-defined epitope-specific monoclonal antibodies in an immunoradiometric assay format, specific and sensitive assays have been developed. Serum levels of free beta-hCG were abnormally high in patients with gestational trophoblastic disease. In contrast, free alpha-hCG levels in serum were not increased.     

Radioimmunoassay of free beta-subunit of human chorionic gonadotropin in diagnosis of high-risk and low-risk gestational trophoblastic disease

A radioimmunoassay was performed with monoclonal antibody 1E5, which distinguishes free beta-subunit of human chorionic gonadotropin in the presence of intact human chorionic gonadotrophin. Serum samples were obtained from 68 pregnant women, 9 with hydatidiform mole who underwent spontaneous remission, 12 with hydatidiform mole who developed gestational trophoblastic disease, 5 with metastatic gestational trophoblastic disease of high-risk category, and 1 with choriocarcinoma concomitant with pregnancy. The concentrations of free beta-subunit of human chorionic gonadotropin and total beta-subunit were determined on the sera. The assay data were expressed as a ratio of nanograms of free beta-subunit per 1000 mIU of total beta-subunit. The ratios, analyzed by the Wilcoxon two-sample test, indicated a highly significant correlation between high ratios and the eventual diagnosis of high-risk gestational trophoblastic disease (p = 0.0019). This study suggests that the excessive production of free beta-subunit of human chorionic gonadotrophin may identify patients with high-risk gestational trophoblastic disease much earlier and identify gestational trophoblastic disease in patients during pregnancy.     

Persistent low levels of human chorionic gonadotropin: A premalignant gestational trophoblastic disease

OBJECTIVE: This study was undertaken to evaluate the significance of persistent low-level human chorionic gonadotropin (hCG) titers (usually <50 IU/L) in the absence of clinical evidence of pregnancy or gestational trophoblastic disease. STUDY DESIGN: The USA hCG Reference Service consulted on 114 cases with persistent low levels of hCG; 51 had false-positive hCG results. The remaining 63 cases had real hCG results and are presented here. RESULTS: Antecedent gestational events included hydatidiform mole (27), pregnancy (35), and gestational trophoblastic neoplasm (1). Forty of the 63 (64%) cases received therapy, including chemotherapy (38), hysterectomy (2), or both (10). Despite treatment, in all cases, low hCG titers persisted. After 1 to 4.5 years of low titers, four women had a sudden rapid increase in hCG levels, and malignant disease was confirmed or clearly suggested (gestational trophoblastic neoplasm [3] and placental site trophoblastic tumor [1]). Invasive trophoblast antigen (ITA) is a marker of invasive cytotrophoblast cells. ITA was measured in 38 of the cases with persistent low hCG, in all cases ITA accounted for less than 25% of the hCG concentration. It was also determined in the 4 cases indicated with malignant disease, accounting for more than 80% of the hCG. CONCLUSION: The presence of persistent low-level hCG titers defines a subset of women with preinvasive or quiescent gestational trophoblastic disease. ITA effectively detected the presence or absence of invasive cells in these cases. The recommended management of the quiescent disease is close surveillance without therapy until malignant disease detected.     

Experience of human chorionic gonadotropin assays in gestational trophoblastic tumors.

From May 1979 through December 1988, 146 patients with gestational trophoblastic tumors (71 hydatidiform mole, 3 partial mole, 15 choriocarcinoma and 57 persistent trophoblastic tumors) were studied. A total of 1178 daily urine samples were collected before and/or after treatment, and in the course of follow-up. H93 RIA (an HCG specific assay), H80 RIA (an assay detecting hCG and hLH) and a hCG alpha assay measured levels in the urine specimens. Three hCG declining patterns (pattern D, P and R) based on the H93 RIA assay were noted. Patients showing pattern D had the most favorable outcome (no mortality at all). However, pattern P and R had a 10% and 14.3% mortality rate, respectively. The ratios of H80/H93, hCG alpha/H93, hCG alpha/H80 in the urine specimens were similar in both pattern D and R (excluding samples from a patient who expired later). However, the ratios of H80/H93, hCG alpha/H93, hCG alpha/H80 of samples from the patient (CK) who expired later were significantly different from those of the pattern D and R. This was suggestive of a marked unbalanced secretion of hCG and its subunit in the urine specimens of patient CK. The molecular forms in pattern D were similar to the standard hCG. However, the molecular form in pattern R of 3 fatal choriocarcinomas showed a great variation, from smaller to larger than the standard hCG. The isoelectric points of hCG in pattern D and R were all acidic. In clinical practice, we can measure the ratios of H80/H93, hCG alpha/H93 and hCG alpha/H80, molecular forms, and isoelectric points of hCG.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gestational trophoblastic disease and human chorionic gonadotropin measurement

Improved radioimmunometric assays for the glycoprotein human chorionic gonadotropin, its whole molecule and free beta and alpha subunits have improved the capability for trophoblast tumor detection and monitoring. New heights in survival rates have been reached with these improvements, particularly in high-risk disease.     

A rapid solid-phase radioimmunoassay specific for human chorionic gonadotropin in gestational trophoblastic disease.

A rapid solid-phase radioimmunoassay (RIA) specific for human chorionic gonadotropin (hCG) has been used for the measurement of serum hCG activity in patients with molar pregnancy and gestational trophoblastic disease (GTD). Serum hCG regression as determined by the specific RIA method after evacuation of uncomplicated molar pregnancy was noted to occur over a longer duration of time than previously reported from this Center using a nonspecific RIA system which measures human luteinizing hormone (hLH) and hCG simultaneously. Therapy for proliferative trophoblastic disease was withheld after evacuation of molar pregnancy while the serum hCG level regressed normally, but was instituted when the serum hCG level rose or plateaued for more than two consecutive weeks. Serum hCG levels in patients requiring chemotherapy for GTD were also more accurately monitored with the specific RIA method than with the nonspecific technic. Therapy was based solely on the hCG titer rather than the subsidence of toxicity, as has been our practice in the past. As a result, the duration of hospitalization, total dose of drug required for remission, and toxic side effects were substantially reduced without sacrificing the effectiveness of chemotherapy.     

Change in human chorionic gonadotropin in gestational trophoblastic disease observed during the course of chemotherapy.

This study investigates the physicochemical characteristics of human chorionic gonadotropin (hCG) in gestational trophoblastic disease (GTD), with special reference to the clinical course of chemotherapy and prognosis. In gel high performance liquid chromatography (HPLC), the hCG molecules from normal pregnancy and from the hydatidiform mole had the same molecular form as standard purified hCG, whereas hCG from choriocarcinoma was inconsistent in molecular form, containing molecules which are smaller, the same or larger than those of standard purified hCG. In two fatal choriocarcinoma patients, large hCG and large hCG alpha were found in the urine samples collected within one month prior to death. In a chromatofocusing study, the chromatofocusing pattern of hCG from GTD was acidic and similar to that of early pregnancy. The chromatofocusing patterns did not alter or were altered only slightly during the course of chemotherapy. In a Concanavalin A-Sepharose (Con A) chromatography study, the Con A binding shifted from low to high binding in patients with GTD who were responsive to chemotherapy. In summary, the molecular form, electric charge and Con A binding of hydatidiform mole hCG are similar to those of early pregnancy hCG and standard purified hCG, whereas the molecular form and Con A binding of choriocarcinoma are different from those of early pregnancy hCG and standard purified hCG. The presence of smaller or larger molecular forms of hCG may be an ominous sign, whereas the presence of high Con A binding may be a favorable sign. The chromatofocusing pattern seems to be unrelated to the clinical course of chemotherapy.     

Management of gestational trophoblastic disease and other cases with low serum levels of human chorionic gonadotropin

Recent publications show that the measurements of particular human chorionic gonadotropin (hCG) variants are extremely beneficial in the diagnosis, monitoring and treatment of gestational trophoblastic disease (GTD). Here we review the possible sources of hCG and the use of commercial tests in the optimal management of GTD, quiescent GTD,false positive hCG results, placental site trophoblastic tumor (PSTT) detection, nontrophoblastic neoplasms and pituitary hCG. Hyperglycosylated hCG (hCG-H) measurements are ideal for discriminating active (invasive) from inactive (quiescent or benign) disease. hCG-H testing is also more sensitive than regular hCG in detecting recurrent or persistent disease. After excluding false positive hCG results, and in the absence of any radiographic evidence of tumor, hCG-H should be measured before starting chemotherapy or surgery in women presenting with low hCG (<1,000 mIU/mL) with or without a history of GTD. The hCG free beta assay is an invaluable test in discriminating PSTT from other GTDs, thereby aiding the determination of appropriate treatment options.     

Circulating antibodies against human chorionic gonadotropin following trophoblastic disease

The presence of antibodies against human chorionic gonadotropin (hCG) is described in a patient who was treated for persistent trophoblastic disease. These antibodies remained detectable over a 14-month period of observation. In 15 other patients, successfully treated for trophoblastic disease, their presence could not be demonstrated. The binding affinity for labeled hCG was investigated by polyethylene glycol precipitation, by complex formation with protein A-Sepharose, and by gel filtration. Circulating antibodies against hCG may interfere with immunological serum hCG estimations.     

Comparison of human chorionic gonadotropin regression in molar pregnancies and post-molar nonmetastatic gestational trophoblastic neoplasia

The rate of regression of the beta subunit of human chorionic gonadotropin in patients successfully treated by single-agent chemotherapy with methotrexate (MTX) for postmolar nonmetastatic gestational trophoblastic neoplasia (NMGTN) has not previously been described. In 21 patients with NMGTN treated with MTX, the rate of regression was determined. Nineteen patients had a log-exponential disappearance of serum beta-hCG titers within 100 days. There was a 50% probability of a negative titer at 50 days. Two patients had plateauing titers within 63 days after therapy. There was no difference in beta-hCG disappearance whether MTX with citrovorum factor or MTX alone was administered. Also, the regression rate of beta-hCG titer in the treated patients was compared to 63 patients with spontaneous decline of titers postevacuation of trophoblastic disease. In the postevacuation group there was a 50% probability at 49 days of negative serum titers. All 63 patients had negative titers within 105 days after evacuation.     

The use of a radioimmunoassay specific for human chorionic gonadotropin in patients with molar pregnancy and gestational trophoblastic disease

Serum human chorionic gonadotropin (hCG) activity is compared in 14 patients under treatment for gestational trophoblastic disease (GTD) using both a radioimmunoassay (RIA) specific for hCG and a nonspecific rapid solid-phase RIA which measures both luteinizing hormone (hLH) and hCG. The results indicate that the nonspecific RIA is adequate for the diagnosis and management of patients with GTD when the hCG titer is above endogenous hLH levels, but a specific RIA is required to ensure complete remission and to detect early recurrence during follow-up.     

Serum methotrexate and human chorionic gonadotropin concentrations during five-day chemotherapy for low-risk metastatic gestational trophoblastic neoplasia

A recent report of serum methotrexate (MTX) levels measured during treatment of gestational trophoblastic neoplasia (GTN) led us to determine MTX and human chorionic gonadotropin (beta-hCG) levels in a patient with low-risk metastatic GTN with a pulmonary metastasis. Peak MTX concentrations exceeded 10(-6) mol/l considered by many investigators to be within the therapeutic range against many human tumors. Serum beta-hCG levels did not decline during MTX administration; however, after 5 days of MTX a steep dose-response curve was observed which continued during 5 courses of chemotherapy.     

Radioimmunoassay of free beta-subunit of human chorionic gonadotropin as a prognostic test for persistent trophoblastic disease in molar pregnancy

A new radioimmunoassay system was established with a monoclonal antibody (1E5) that distinguishes the free beta-subunit of human chorionic gonadotropin in the presence of intact human chorionic gonadotropin, showing only 0.23% cross-reactivity with the intact human chorionic gonadotropin molecule and virtually no cross-reactivity with other glycoprotein hormones or their beta-subunits. Serum samples, taken at initial diagnosis from nine patients with hydatidiform mole and spontaneous remission and 12 patients with subsequent progression to persistent trophoblastic disease, were assayed for free and total levels of the beta-subunit of human chorionic gonadotropin. The assay results were expressed as a ratio of nanograms of free beta-subunit per 1000 mIU of total beta-subunit. Eight of nine patients with mole and spontaneous remission had a ratio value less than 4 whereas 10 of 12 patients with subsequent persistent disease had a ratio value greater than 4. Statistical analysis with chi 2 showed a highly significant correlation of high ratios with eventual progressive disease (p = 0.0009). This study suggests that excessive production of the free beta-subunit of human chorionic gonadotropin may identify patients with a high likelihood of developing persistent trophoblastic disease.     

Monitor of chemotherapy in gestational trophoblastic neoplasm by radioimmunoassay of the beta-subunit of human chorionic gonadotropin.

Radioimmunoassays and bioassays based on the reactions of the native molecule of human chorionic gonadotropin (HCG) fail to differentiate HCG from pituitary luteinizing hormone (LH). An assay based on the beta-subunit of HCG which detects HCG exclusively has been used in our laboratory to monitor patients undergoing chemotherapy for gestational trophoblastic disease (GTD). We have been able to differentiate minimal, persisting tumor activity from normal levels of pituitary gonadotropins and have based therapy on these findings. Alternatively, treatment has been terminated when HCG is no longer detectable in the serum. Tumor activity has been detected in the beta-subunit assay at a time when biologic activity in the urine indicated remission.